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Recommended phase 2 dose and schedule of alisertib (MLN8237) in combination with rituximab based on safety and tolerability (phase 1, part 1) [ Time Frame: From the screening period to 30 days after the last dose of alisertib (MLN8237), approximately 6 months ]

Recommended phase 2 dose and schedule of alisertib (MLN8237) in combination with rituximab and vincristine based on safety and tolerability (phase 1, part 2) [ Time Frame: From the screening period to 30 days after the last dose of alisertib (MLN8237), approximately 6 months ]

Number of patients with overall response (phase 2) [ Time Frame: At the end of Cycle 2, at the end of every second treatment cycle until 6 months, then every 12 weeks thereafter, approximately 2 years ]

Number of patients with overall response (phase 1, part 1) [ Time Frame: At the end of Cycle 2, at the end of every second treatment cycle until 6 months, then every 12 weeks thereafter, approximately 2 years ]

Complete response + partial response

Number of patients with overall response (phase 1, part 1 & 2) [ Time Frame: At the end of Cycle 2, at the end of every second treatment cycle until 6 months, then every 12 weeks thereafter, approximately 2 years ]

Complete response + partial response

Number of patients with complete response, duration of response, and progression free survival (phase 2) [ Time Frame: Duration of study until disease progression, approximately 2 years ]

Number of adverse events and results of vital signs, electrocardiograms (ECGs), multigated acquisition (MUGA)/ echocardiogram (ECHO), physical examination and laboratory tests (phase 2) [ Time Frame: From screening period to 30 days after last dose of study drug, approximately 2 years ]

Safety and tolerability of alisertib (MLN8237) treatment

Maximum plasma concentration (Cmax) (phase 1, parts 1&2) [ Time Frame: Cycle 1 Day 1 and Day 7, then Day 8 of each treatment cycle, approximately 6 months ]

Pharmacokinetic parameters of alisertib (MLN8237)

Time to maximum plasma concentration (Tmax) (phase 1, parts 1&2) [ Time Frame: Cycle 1 Day 1 and Day 7, then Day 8 of each treatment cycle, approximately 6 months ]

Pharmacokinetic parameters of alisertib (MLN8237)

Area under the plasma concentration versus time curve over the dosing interval (AUC0-τ) (phase 1, parts 1&2) [ Time Frame: Cycle 1 Day 1 and Day 7, then Day 8 of each treatment cycle, approximately 6 months ]

A Multicenter, Phase 1-2 Study of MLN8237, an Oral Aurora A Kinase Inhibitor, in Patients With Relapsed or Refractory Aggressive B-Cell Lymphoma Treated With Rituximab and Vincristine

Brief Summary

This is a single-arm, open-label, multicenter, dose escalation, phase 1-2 study of alisertib (MLN8237) administered in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)/transformed follicular lymphoma (TFL) treated with rituximab and vincristine. The study has three parts as follows:

Phase 1, Part 1: Safety lead-in cohort combining alisertib (MLN8237) as an enteric coated tablet (ECT) orally twice/day Days 1-7 & rituximab as an intravenous (IV) infusion on Day 1 in a 21 Day cycle for up to 8 cycles

Phase 1, Part 2: Alisertib (MLN8237) as an ECT orally twice/day Days 1-7 & rituximab as an IV infusion on Day 1 & vincristine IV Days 1 & 8 in a 21 Day cycle for up to 8 cycles

Phase 2: Alisertib (MLN8237) as an ECT orally twice/day Days 1-7 & rituximab as an IV infusion on Day 1 & vincristine IV Days 1 & 8 in a 21 Day cycle for up to 8 cycles

Following 8 cycles of treatment (or early discontinuation of rituximab) all patients with documented disease response or stabilization may continue with alisertib (MLN8237) single-agent therapy up to 2 years

Study Arms

Experimental: Alisertib (MLN8237) + Rituximab + Vincristine

Intervention: Drug: Alisertib (MLN8237) + Rituximab + Vincristine

Publications *

Not Provided

* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Relapsed after autologous stem cell transplantation or not be eligible for autologous stem cell transplantation or refuse autologous stem cell transplantation. Patients enrolled to the phase 2 part must have received prior rituximab.

Female patients who are post menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 30 days after the last dose of alisertib (MLN8237) or agree to abstain from heterosexual intercourse. Patients should also use effective contraception for 12 months following the last dose of rituximab and 1 month following the last dose of alisertib (MLN8237.

Male patients who agree to practice effective barrier contraception through 4 months after the last dose of MLN8237 or agree to abstain from heterosexual intercourse

Patients who have undergone allogeneic stem cell or organ transplantation any time

Systemic antineoplastic therapy, including glucocorticoids or treatment with an investigational agent within 14 days preceding the first dose of study drug treatment. Steroids are permitted for administration with rituximab to prevent or treat infusion reaction

Treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment within 42 days (21 days if clear evidence of progressive disease) prior to the first day of study drug treatment

Treatment with radioimmunoconjugates or toxin immunoconjugates, such as ibritumomab-tiuxetan, or tositumomab, within 12 weeks prior to the first day of study drug treatment

Radiotherapy within 21 days prior to the first dose of study drug treatment

Treatment with enzyme-inducing antiepileptic drugs, such as phenytoin, carbamazepine, or phenobarbital, or with rifampin, rifabutin, rifapentine, or St. John's wort, within 14 days prior to the first dose of alisertib (MLN8237) also not permitted during study

Cardiac status as described in protocol

Major surgery, serious infection, or infection requiring systemic antibiotic therapy within 14 days prior to the first dose of study treatment

History of hemorrhagic or thrombotic cerebrovascular event in the past 12 months

Clinically uncontrolled central nervous system involvement

Inability to receive IV rituximab or vincristine, or to swallow tablets or inability or unwillingness to avoid taking anything by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of alisertib (MLN8237)

History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness

Female patients who are lactating or pregnant

Serious medical or psychiatric illness or laboratory abnormality that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol

Clinically apparent ≥ Grade 2 neuropathy due to any cause in the 3 months prior to enrollment, or history of ≥ Grade 3 neuropathy related to vincristine at any time